Pharmacotherapy of Pain The Pain Pathway 1.) Peripheral nociceptors •bradykinin, substance P, histamine, acetylcholine, serotonin, ↓ pH (H+), prostaglandins (inflammatory mediators) 2.) Primary afferent fibres → dorsal horn of spinal cord •substance P, neurokinin A, glutamate •Inhibition of pain transmission on spinal level = descending pathways from midbrain and medulla to dorsal horn (serotonine, noradrenaline, GABA, enkefalins…) 3.) Spinothalamic and spinorecticular tract (spine → thalamus/brainstem reticular formation) •Localisation a emotional aspects of pain 4.) Thalamocortical pathway (thalamus → cortex) •Localisation, cause of pain + coordination of a response NSAIDs •Non-steroidal antiinflammatory drugs •Inhibition of cyclooxygenase = ↓ prostaglandins •Treatment of „common“ pain, inflammatory diseases (gout, rheumatoid arthritis etc.), reduction of fever, combination of analgesics in stronger pain •Administration – p.o., rectal, topical, parenteral •Binding to plasma proteins – possible interactions •Good GIT absorption, passage into the synovial fluid, through BBB, placenta… Classification: 1.) NON-SELECTIVE (COX1 ~ COX2) 2.) PREFERENTIAL (COX1 < COX2) 3.) SELECTIVE (COX1 <<< COX2) Cyclooxygenase •Isoenzymes: physiological, inducible, (CNS?) • •COX1 – protection of gastric mucosa, kidney vasodilation, aggregation of thrombocytes •COX2 – site of inflammation, expressed due to ILs and TNF-α •COX3 – CNS? Phospholipids Arachidonic acid Cyclic endoperoxides LEUKOTRIENS PROSTAGLANDINS PROSTACYCLIN TROMBOXANS LOX COX Essential FA Phospholipase A2 + NOXIOUS STIMULI – LIPOCORTIN (ANNEXIN) Glucocorticoids NSAIDs – allergy, leucotaxis vasodilation, inhibition of thrombocytes aggregation vasoconstriction, ↑ thrombocytes aggregation pain, inflammation, ↓ HCl, ↑ gastric mucus, uterus contractions, ↑ kidney perfusion, ↑ excretion of Na+ and water Acetylsalicylic acid •non-selective, irreversible COX inhibitor •plasmatic esterases: ASA → SA + AA •30-100 mg antiaggregant, 500 mg analgesic-antipyretic, over 1000 mg antiphlogistic •gastric absorption, possible irritation and ulceration of GIT (MoA + acidity), renal excretion •contraindications: children up to 12 years old – Reye‘s syndrome gastric ulcers, asthma before surgery •elderly – more susceptible to AE •„aspirin asthma“ = leucotriens predominance •other salicylates: choline salicylate, sulfasalazine… Paracetamol (Acetaminophen) •analgesic-antipyretic = without antiphlogistic and antiaggregant activity, no gastrotoxicity •mechanism of action unclear: •COX3? serotonin? TRPV ion channels? •dose: 10-15 mg/kg – frequently underdosed! •max. dose 4000 mg (8 tablets à 500 mg) •hepatotoxicity = NAPQI, detoxification by glutathione •overdosing – N-acetylcysteine therapy •combinations with tramadol, codein, propyphenazone, antispasmodics •suitable for children, elderly Acetic Acid Derivatives —Diclophenac ‒joint diseases → passage into synovial fluid ‒shorter half-life, capsules with prolonged release ‒cardiotoxicity – higher doses, contraindication —Aceclofenac ‒oral use only in the treatment of joint diseases ‒relatively low gastrotoxicity ‒also contraindicated for patients with CVD —Indomethacin ‒strong effect, only for short-term treatment ‒uricosuric effect = ↑ excretion of uric acid in the urine ‒used in acute gout attack ‒↑ gastrotoxicity, changes in blood count, headache and CNS disorders (all of them very frequent) ‒contraindicated for children Propionic Acid Derivatives Ibuprofen – good tolerability, safe ‒200-400 mg analgesic, antipyretic ‒1400-1600 mg antiphlogistic ‒max. dose 2400 mg ‒suitable for children Ketoprofen – topical use (skin phototoxicity!) Dexketoprofen – oral use Flurbiprofen – topical oral use (lozenges/pastilles) Naproxen – relatively low gastrotoxicity, longer half-life, good for headache and toothache Other Important Analgesics Propyphenazone – with paracetamol and caffeine Metamizole •analgesic-antipyretic with mild antispasmodic effect •no antiphlogistic effect •myelotoxicity (changes in BC) → only for short-term use •combinations with antispasmodics (e.g. pitofenone, fenpiverinium) Oxicams – long biological half-life: •Piroxicam – topical use, very long half-life (high risk of accumulation if taken orally) •Meloxicam – preferential effect on COX2 •joint diseases – good passage into synovial fluid •reduction of GIT adverse effects •Lornoxicam – non-selective effect on COX Preferential COX2 Inhibitors •COX1 < COX2 •reduction of GIT adverse effects •analgesic, antiphlogistic and antiaggregant effect • Nimesulide •inhibits also collagenases and elastases degrading cartilages + ROS scavenger •hepatotoxicity → only for short-term use (15 days) Meloxicam Selective COX2 Inhibitors = Coxibs •COX1 <<< COX2 •minimal GIT adverse effects •joint diseases • •cardiovascular AE – thrombotic diseases (due to inhibition of prostacyclin in endothelia) •contraindicated for patients with CVD •some of them withdrawn and lost market authorisation for severe CV and skin AE (rofecoxib) • •celecoxib, parecoxib, etoricoxib Protection against NSAIDs toxicity •use of safe dosage •fight against overuse, misuse, „dependence“ •protection of gastric and intestinal mucosa (PPI – omeprazole) •education of both patients and health professionals •avoidance of drug-drug interactions graf umrti NSAIDs.gif Opioid analgesics Opiod analgesics = anodynes lOPIUM – Papaver somniferum, Papaveraceae lBind to opiod receptors – changes in ion homeostasis of neurons → hyperpolarization, inability to conduct electrical impulses + changes in GABA signalling in specific parts of the brain — —OPIOID RECEPTORS: — —μ [mu] – supraspinal and spinal analgesia — —κ [kappa] – spinal and peripheral analgesia — —δ [delta] – spinal analgesia — — —σ [sigma] – dysphoria, hallucinations, changes in perception (not an opioid receptor, bud some opioids have affinity for it) Classification of Opioids —According to their receptor effects: —1.) Agonists: a) strong effect (morphine, pethidine, methadone, fentanyl) b) medium and mild effect (codeine, dextropropoxyphene) —2.) Partial agonists (buprenorphine) and agonists-antagonists (butorphanol) —3.) Atypical opioids (tramadol, tilidine, tapentadol) —4.) Antagonists (naloxone, naltrexone) — —According to their origin: a) endogenous (enkephalins, endorphins, dynorphins) b) natural (morphine, codeine…) c) semisynthetic (oxycodon, dihydrocodeine…) d) synthetic (pethidine, butorphanol, methadone, fentanyl...) Opioid Agonists: Effects •mostly originate from activation of μ receptors —Central effects: •depression of CNS: sedation → somnolence → coma •depression of breathing – ↓ sensitivity of respiratory center •antitussive effect – ↓ sensitivity of cough center •emesis, nausea – first doses, irritation of area postrema •miosis – via n. oculomotorius •changes in hormonal levels: cortisol, ADH, GnRH → FSH, LH, testosteron…) —Peripheral effects: •↑ smooth muscle tone – constipation, urine retention, spasm of sphincters in GIT and GUT (contraindicated for colics!) •CVS – histamine liberation, vazodilation, postural hypotension •RESP – possible bronchoconstriction (histamine) • Opioid Agonists —Pharmacokinetics: •good absorption from GIT, but frequently high first pass effect (= not suitable for oral use) •pharmacologically active metabolites (e.g. codeine) —Addictive potential •dependency producing substances •tolerance – need for higher doses •craving for another dose •abstinence syndrome •Act No. 167/1998 Coll. on Dependency Producing Substances •instructions for prescription and use •methadone – substitution therapy for the addicted Opioid Agonists with Strong Effect •MORPHINE – 10 mg i.m., s.c., p.o., lasts 4-5 h •METHADONE – longer half-life, substitution therapy •OXYCODON, HYDROCODON •with paracetamol (acetaminophen) •PETHIDINE —Fentanils •the most effective opioids •lipophilic → good absorption •shorter effect → infusions, TTS •anesthesiology, algesiology •FENTANYL or FENTANIL •SUFENTANIL – 500 times more effective than morphine Opioid Agonists with Medium and Mild Effect —CODEINE •metabolised to morphine •analgesic – combined therapy (paracetamol) •antitussive: 10-30 mg •decreases secretion in bronchi and bronchioles •contraindicated for children —DIHYDROCODEINE •cancer pain •tablets with prolonged release Partial agonists and Agonists-Antagonists —BUPRENORPHINE •partial agonist of μ opioid receptors •strong FP effect – parenteral administration (buccal tablets) •RMP Suboxone – combination therapy with naloxone (opioid addiction) —BUTORPHANOL — —PENTAZOCINE •κ a δ agonist •μ antagonist •mild analgesic effect •σ and κ activation = hallucinations, euforia, dysforia, abnormal dreams •↓ AE, ↓ dependency •mild analgesic effect Atypical Opioids —TRAMADOL •low affinity for μ receptors + blockade of 5-HT and NA re-uptake (neurotransmitters of pain pathway) •max. dose 600 mg •frequently causes nausea and emesis •oral drops, tablets, modified release •advantages: no attenuation of respiratory center — no constipation — —TILIDIN, TAPENTADOL Opioid Antagonists •treatment of acute opioid intoxication and overdosing •treatment of addiction to opioids, heroin •treatment of alcohol addiction (nalmefene) •quick effect (in minutes), lasts 2-3 h •parenteral use, oral use (nalmefene) • —NALOXONE —NALTREXONE — —NALMEFENE Strategy in the Treatment of Pain — —1. CAUSAL TREATMENT •cause of pain — —2. SYMPTOMATIC TREATMENT •pain itself WHO PAIN LADDER Anti-rheumatics – Therapy of RA —DMARDs – disease-modifying antirheumatic drugs •SULFASALAZINE ‒bowel microflora decomposition → 5-aminosalicylic acid and sulfapyridine •GOLD COMPOUNDS ‒e.g. sodium aurothiomalate ‒inhibition of phagocytosis •CHOLOROQUIN ‒originally for treatment and prevention of malaria ‒inhibition of chemotaxis of leukocytes •METHOTREXATE ‒immunosupressive therapy ‒folic acid antimetabolite ‒used in high dosis as cytostatic drug (cancer therapy) ‒highly effective ‒effect starts after 3-4 weeks • Anti-rheumatics —Targeted therapy: •Targeted interference with immune cells and mediators •Monoclonal antibodies, genetically engineered proteins… •Expensive, prescribed only when conventional treatment fails •Mechanisms of action: •anti-TNF-α drugs: ADALIMUMAB, infliximab, etanercept, certolizumab, golimumab •blockade of IL-6 receptor: tocilizumab •blockade of IL-1 receptor: anakinra •interference with T and B lymphocytes: abatacept, rituximab —NSAIDs: •Alleviation of morning joint stiffness •Analgesic and antiinflammatory effect •DICLOFENAC, IBUPROFEN; MELOXICAM, CELECOXIB and the others…